Desmopressin Dose Requirements in Adults with Congenital and Acquired Central Diabetes Insipidus.

Central diabetes insipidus is a rare disorder characterized by a deficiency of vasopressin. The first line drug to treat this disorder is a synthetic analogue of vasopressin, desmopressin.The primary aim of this retrospective register study was to compare desmopressin dose requirements in patients with acquired and congenital DI, and secondly to assess the influence of BMI on dose requirement and risk of hyponatremia with different drug administrations. We included all patients with suspected DI attending the endocrine department at Rigshospitalet, Copenhagen, Denmark in 2022. We identified 222 patients who were included whereof 130/222 (58.6%) were females and median age was 53 years (IQR 35 to 63). The etiology included 7/222 (3.2%) congenital and 215/222 (96.8%) acquired. After converting nasal and sublingual doses to equivalent oral doses, the median daily dose requirement was 600 µg in patients with congenital etiology compared to 200 µg in patients with acquired etiology (p=0.005). We found no association between BMI and desmopressin dose requirements (p=0.6). During the past 12 months, 66/215 (30.7%) had sodium levels<136 mmol/l including 20/215 (9.3%) with sodium levels<131 mmol/l. No increased risk of hyponatremia was found, when nasal and oral were compared (p=0.9). Daily desmopressin dose requirements were higher in patients with congenital DI compared to patients with acquired DI. However, this result was associated with uncertainty due to the small congenital group. BMI did not influence daily dose requirements and nor did type of administration influence the risk of hyponatremia.

Efficacy and safety of desmopressin in nocturia and nocturnal polyuria control of neurological patients: A systematic review and meta-analysis.

PURPOSE: Evidence on the efficacy of desmopressin in nocturia in patients with neurological diseases is still very limited except for multiple sclerosis (MS). Our aim was to evaluate the efficacy and safety of desmopressin treatment on nocturia in patients with underlying neurological diseases. METHODS: Studies were identified by electronic search of PubMed, Embase, Cochrane, CINAHL, and Google Scholar databases. Studies were considered if they provided information on the effectiveness and safety of desmopressin (1-desamino-8-d-arginine vasopressin, or DDAVP) in the treatment of nocturia and their participants had acquired neurological pathology. Two researchers independently extracted the articles using specified datasets, such as quality-of-study indicators. Statistical meta-analysis was carried out using Review Manager (RevMan) 5.4 statistical software (Cochrane Collaboration). RESULTS: Of a total of 1042 articles in the initial search, 14 studies were included. Most of the published papers were related to MS (n = 7), two were on spinal cord injury, and other conditions were neural tube defect, myelodysplasia, Parkinson's disease, stroke, and multiple system atrophy. Overall, a total of 200 patients (mostly females) were enrolled. Thirteen studies evaluated the intranasal formulation of desmopressin and one study evaluated oral desmopressin. A significant decrease in nocturia episodes was reported in seven studies evaluating this topic. An increase in the maximum hours of uninterrupted sleep was reported in the three studies in which this outcome was assessed. A significant reduction in the volume of nocturnal incontinence was found in one study. Three studies were eligible to include in the meta-analysis. The results showed that desmopressin compared to placebo, significantly reduced nighttime urination (mean difference: -0.75, 95% CI: -1.10 to -0.41; p < 0.00001). The rate of adverse events ranged from 0% to 68.42%. The critical appraisal results for all trials showed that most of the studies had low or moderate quality. CONCLUSIONS: Our results emphasized desmopressin's safety and efficacy in reducing nocturia episodes, with transient adverse effects on neurological patients. However, the data were achieved from low or medium-quality trials, and further well-designed randomized controlled trials are needed.

Desmopressin therapy in children and adults: pharmacological considerations and clinical implications.

PURPOSE: This review aims to provide prescribing clinicians a deeper appreciation of desmopressin's clinical indications and formulation types, to better balance efficacy and safety through proper formulation selection. BACKGROUND: Since its discovery 50 years ago, desmopressin's antidiuretic properties have been used for central diabetes insipidus, primary monosymptomatic nocturnal enuresis and adult nocturnal polyuria, while its coagulant effects are useful for mild hemophilia A and von Willebrand Disease. During this time, newer formulations of desmopressin have also been introduced to the market raising questions on interchangeability, dose conversion and safety. The wide array of clinical indications and variable pharmacokinetic properties of different desmopressin preparations raises the possibility of medication error, especially the risk of hyponatraemia. METHODOLOGY: A narrative review to explore clinically relevant aspects of desmopressin therapy, synthesising information obtained from searches of published literature. RESULTS: We identified that the risk factors for developing hyponatremia include extremes of age, existing comorbidity, drug interaction, intranasal formulations and intercurrent illness. We describe the dose equivalence between all formulations to facilitate conversion. We highlight that in view of inter-subject variability, close monitoring is recommended when switching preparations. We found that paediatric data remains limited, leading to recent proposals for age- and weight-based dosing regimens. CONCLUSION: The risk of hyponatremia, albeit small, can be reduced by adhering to the indication-specific doses and taking steps to govern the safe prescription of the drug. Further paediatric clinical trials are awaited to expand the evidence base of childhood desmopressin therapy.

Vasopressin Administration Is Associated With Rising Serum Lactate Levels in Patients With Sepsis.

BACKGROUND: Vasopressin is used in conjunction with norepinephrine during treatment of patients with septic shock. Serum lactate is often used in monitoring of patients with sepsis; however, its importance as a therapeutic target is unclear. The objective of this study is to examine the relationship of vasopressin use on serum lactate levels in patients with sepsis. METHODS: This study uses electronic heath records available via the Medical Information Mart for Intensive Care III. Patients were required to have a serum lactate monitoring during the intensive care unit (ICU) stay. The treatment was the administration of vasopressin between hours 3 and 18 of the ICU stay. Analysis was performed using a matched design. RESULTS: Patients receiving vasopressin were more likely to have their serum lactate levels rise when compared to matched patients who did not receive vasopressin (odds ratio: 6.6; 95% confidence interval: 3.0-14.6, P < .001). Patients who received vasopressin had a median increase in serum lactate of 0.3 mmol/L, while patients who did not receive vasopressin had a median decrease in serum lactate of 0.7 mmol/L (P < .001). There was no statistically significant difference between the control and treated groups' lactate trajectories prior to possible administration of vasopressin (P = .15). The results did not change significantly when norepinephrine initiation was used as the index time. CONCLUSIONS: In patients with sepsis, the administration of vasopressin was associated with a statistically significant difference in lactate change over the course of 24 hours when compared to matched patients who did not receive vasopressin.

Pharmacokinetic and Pharmacodynamic Properties of a Micro-Dose Nasal Spray Formulation of Desmopressin (AV002) in Healthy Water-Loaded Subjects.

PURPOSE: Antidiuretic therapy with desmopressin for nocturia has been hampered by formulations with high doses, low bioavailability and variable pharmacokinetics. AV002 (SER120), a novel, emulsified, microdose desmopressin nasal spray, with a permeation enhancer (cylcopentadecanolide), was developed to have pharmacokinetic characteristics suitable for nocturia treatment. METHODS: Twelve healthy subjects participated in an open-label, dose-escalating study. Water-loaded subjects were sequentially dosed every 48 h with AV002 0.5, 1.0, 2.0 µg and 0.12 µg desmopressin subcutaneous (SC) bolus injection. RESULTS: AV002 intranasal administration produced a time-to-maximum concentration (Tmax) between 15 and 30 min and a maximum concentration (Cmax) <10 pg/mL. Cmax and area under the curve showed dose proportionality. Coefficient of variation for AV002 was similar to that observed for the SC dose. Bioavailability of AV002 was approximately 8% compared to SC injection. AV002 demonstrated pharmacodynamic effects within 20 min of dosing and showed increasing magnitude and duration with escalating doses. AV002 2.0 µg had maximum median urine osmolality of 629 mOsm/kg and median urine output ≤2 mL/min for 5-6 h. CONCLUSIONS: AV002 demonstrated rapid absorption, high bioavailability, limited duration of action, and low coefficient of variation, suggesting it may be a suitable formulation for nocturia treatment. Trial registration not required (single-center, phase 1).

Efficacy and Safety of SER120 Nasal Spray in Patients with Nocturia: Pooled Analysis of 2 Randomized, Double-Blind, Placebo Controlled, Phase 3 Trials.

PURPOSE: SER120 desmopressin intranasal spray is the first U.S. Food and Drug Administration approved pharmacotherapy for nocturia. We evaluated its efficacy and safety in 2 randomized, double-blind, placebo controlled studies, DB3 and DB4. MATERIALS AND METHODS: A total of 1,333 intent to treat patients 50 years old or older with 2.16 or more nocturic voids per night during a 2-week screening period were randomized equally to SER120 intranasal spray 1.66 or 0.83 mcg, or placebo for a 12-week treatment. Co-primary end points were the mean change from baseline in nocturic episodes per night and the percent of patients with a 50% or greater reduction in mean nocturic episodes per night. Secondary end points were the validated INTU (Impact of Nighttime Urination) quality of life questionnaire in DB4, time to the first nocturic void and the percent of nights with 1 or fewer nocturic voids. RESULTS: Each SER120 dose showed statistical significance vs placebo for the 2 co-primary end points, including the mean nocturic episodes per night (-1.4 with 0.83 mcg and -1.5 with 1.66 mcg vs -1.2 with placebo, each p <0.0001), the percent of patients with a 50% or greater reduction in mean nocturic episodes per night (37.9% with 0.83 mcg and 48.7% with 1.66 mcg vs 30.3% with placebo, p = 0.0227 and <0.0001, respectively) as well as for all secondary end points in the pooled analyses. The 1.66 mcg dose demonstrated significant improvements in the INTU score (p = 0.0255). The incidence of hyponatremia, defined as serum sodium 125 mmol/l or less regardless of symptoms or less than 130 mmol/l with symptoms, was 1.1%, 0% and 0.2% in the 1.66 and 0.83 mcg, and placebo groups, respectively. Other adverse events were similar across treatment groups. CONCLUSIONS: SER120 demonstrated significant improvements over placebo for co-primary and secondary efficacy end points that corresponded with quality of life improvements. SER120 at each dose had an acceptable safety profile.

Pharmacokinetics and safety profile of desmopressin oral tablet formulations in healthy Chinese subjects under fasting and fed conditions.

OBJECTIVE: Desmopressin acetate (DDAVP®) is a synthetic analogue of the pituitary hormone vasopressin. Until now, few studies of desmopressin have focused on the pharmacokinetics (PK) or food effects in Asian populations. This study aimed to assess the effect of food intake on the PK of desmopressin and bioequivalence of two tablet formulations in Chinese subjects. MATERIALS AND METHODS: A single-center, single-dose, randomized, open-label, two-period crossover study was conducted in 104 healthy Chinese volunteers under fasted or fed conditions (52 volunteers for each condition). Blood samples were collected up to 14 hours after administration of oral desmopressin tablets (0.6 mg; 0.2 mg × 3) in each period. Plasma desmopressin concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK and bioavailability parameters were calculated. Adverse events (AEs) were also recorded. RESULTS: No significant differences in mean (standard deviation, SD) PK parameters were observed between formulation 1 (F1) and formulation 2 (DDAVP®; F2) under both fasted and fed conditions. All AEs observed were mild and resolved quickly without treatment. The maximum concentration (Cmax) and area under the curve (AUC) were significantly decreased (p < 0.01) when the drug was taken with food, compared with fasted subjects. CONCLUSION: These findings suggest that both tablet formulations were well tolerated. Food can significantly decrease the exposure of desmopressin.
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Reset Osmostat: The Result of Chronic Desmopressin Abuse?

A reset osmostat as a cause of hyponatremia can be found in a variety of clinical settings, including pulmonary and neurologic diseases, as well as in physiologic circumstances such as pregnancy. This teaching case describes a 72-year-old white man with a long-standing history of self-medicating with desmopressin acetate (DDAVP) who presented with profound hyponatremia. On discontinuation of DDAVP treatment, he was found to have a reset osmostat. The mild hyponatremia persisted on follow-up. We theorize that the reset osmostat may have developed secondary to long-standing DDAVP use.

Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia.

OBJECTIVE: To explore risk factors for desmopressin-induced hyponatraemia and evaluate the impact of a serum sodium monitoring plan. SUBJECTS AND METHODS: This was a meta-analysis of data from three clinical trials of desmopressin in nocturia. Patients received placebo or desmopressin orally disintegrating tablet (ODT; 10-100 µg). The incidence of serum sodium <130 mmol/L was recorded by age, sex and dose. Potential predictors of clinically significant hyponatraemia were identified using multivariate analysis in a Cox proportional hazards model. RESULTS: Dose, age, baseline serum sodium level and kidney function, according to estimated GFR clearance, were significant risk factors for hyponatraemia in both sexes; similar to the known risk factors associated with hyponatraemia in the general population. In men, arthritis and use of drugs for bone disease were also predictive of hyponatraemia, while in women, raised monocytes and absence of lipid-modifying drugs increased the risk of hyponatraemia. Use of the proposed monitoring scheme and the minimum effective dose would have omitted all patients with clinically significant hyponatraemia from further treatment. CONCLUSIONS: The incidence of hyponatraemia can be reduced by using minimum effective gender-specific dosing with the ODT formulation of desmopressin (25 µg in women, 50 µg in men). A sodium monitoring plan is proposed whereby baseline sodium must be ≥135 mmol/L (especially important in the elderly), with additional monitoring at week 1 and month 1 for those at elevated risk because they are aged ≥65 years or receiving concomitant medication associated with hyponatraemia. This monitoring plan would help to prevent some at-risk patients developing hyponatraemia; retrospective application of the monitoring plan showed that, once at-risk patients were appropriately screened out, only mild, non-clinically significant hyponatraemia was observed, within ranges of other drugs associated with hyponatraemia and similar to the background prevalence in the treatment population.

Desmopressin for treating nocturia in men.

BACKGROUND: Nocturia is the bothersome symptom of awakening one or more times per night to void. Desmopressin is a commonly used medication for treating nocturia. OBJECTIVES: To assess the effects of desmopressin as compared to other interventions in the treatment of nocturia in men. SEARCH METHODS: We performed a comprehensive search of medical literature with no restrictions on the language of publication or publication status. The date of the latest search of all databases was August 2017. SELECTION CRITERIA: We included randomized or quasi-randomized trials. Inclusion criteria were men with nocturia defined as one or more voids per night. Trials of children, adults with primary or secondary enuresis or underlying distinct disorders were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies and abstracted data from the included studies. We performed statistical analyses using a random-effects model and interpreted data according to the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We included 14 studies with 2966 randomized men across five comparisons. Desmopressin versus placebo: based on short-term follow-up (up to three months), desmopressin may have a similar effect on the number of nocturnal voids (mean difference (MD) -0.46, 95% confidence interval (CI) -0.94 to 0.01; low-quality evidence). We are uncertain about the effect of desmopressin on major adverse events at short-term follow-up (risk ratio (RR) 0.97, 95% CI 0.10 to 9.03; very low-quality evidence). For intermediate-term follow-up (three to 12 months), desmopressin may reduce the number of nocturnal voids in an appreciable number of participants (MD -0.85, 95% CI -1.17 to -0.53; low-quality evidence). Desmopressin may result in little or no difference in major adverse events at intermediate-term follow-up (RR 3.05, 95% CI 0.13 to 73.39; low-quality evidence). We found no evidence on quality of life. Subgroup analyses suggest a larger effect with oral, higher-dose formulations of desmopressin and in men with documented nocturnal polyuria. Desmopressin versus behavior modification: there were no data regarding the effect on the number of nocturnal voids, quality of life, or major adverse events. Desmopressin versus alpha-blocker: based on short-term follow-up, desmopressin likely has a similar effect on the number of nocturnal voids (MD 0.30, 95% CI -0.20 to 0.80; moderate-quality evidence) and quality of life (MD 0.00, 95% CI -0.35 to 0.35; moderate-quality evidence). There were no major adverse events in either study group. Desmopressin plus alpha-blocker versus alpha-blocker alone: based on short-term follow-up, combination therapy likely results in a small, unimportant reduction in the number of nocturnal voids (MD -0.47, 95% CI -0.73 to -0.21; moderate-quality evidence) and quality of life (MD -0.29, 95% CI -0.51 to -0.07; moderate-quality evidence). The risk of major adverse events may be similar (RR 0.30, 95% CI 0.01 to 7.32; low-quality evidence). Desmopressin plus alpha-blocker versus alpha-blocker plus an anticholinergic: based on short-term follow-up, combination therapy likely results in little or no difference in the number of nocturnal voids (MD -0.43, 95% CI -0.97 to 0.11; moderate-quality evidence). We found no evidence on quality of life. There were no major adverse events in either study group. AUTHORS' CONCLUSIONS: Desmopressin may reduce the number of nocturnal voids in an appreciable number of participants compared to placebo in intermediate-term (three to 12 months) follow-up without increase in major adverse events. We found no evidence to compare its effects to behavior modification. The effect on the number of nocturnal voids is likely similar to that of alpha-blockers short-term with very infrequent major adverse events. There appears to be no added benefit in the combined use of desmopressin with an alpha-blocker or an anticholinergic. The findings of this review were limited by short-term follow-up, study limitations, and imprecision.

Managing hyponatraemia secondary to primary polydipsia: beware too rapid correction of hyponatraemia.

We describe three cases of severe hyponatraemia in the setting of primary polydipsia that were managed in our centre in 2016. Despite receiving different solute loads, large volume diuresis and rapid correction of serum sodium occurred in all cases. Given the potentially catastrophic consequence of osmotic demyelination, we highlight the judicious use of desmopressin and hypotonic fluid infusion to mitigate sodium overcorrection in this setting.

The risk of hyponatremia with desmopressin use for nocturnal polyuria.

BACKGROUND: Desmopressin is used for treating nocturnal polyuria, but hyponatremia is an associated concern in the elderly due to impaired urinary dilution. This study was undertaken to characterize hyponatremia occurring in adults using desmopressin for nocturnal polyuria. METHODS: Data from 172 patients who were prescribed desmopressin for nocturnal polyuria at a urology clinic from September 2010 through February 2013 were retrospectively analyzed. Demographic and laboratory parameters were investigated to examine the risk factors for desmopressin-associated hyponatremia. RESULTS: The average follow-up serum sodium measured 21 ± 22 days after using desmopressin was 138 ± 5 mmol/l. Hyponatremia (<135 mmol/l) was found in 24 patients (14%), and it was severe in 7 (<126 mmol/l). In the hyponatremic patients, serum sodium decreased by 11 ± 6 mmol/l. Patients with hyponatremia were older than those with normonatremia (78 ± 7 vs. 68 ± 9 years, p < 0.0001). The presence of either hyponatremia-predisposing comorbidities or concurrent medications was associated with hyponatremia. Patients with hyponatremia had lower basal hemoglobin (11 ± 2 vs. 13 ± 2 g/dl, p < 0.001) and serum sodium (139 ± 2 vs. 140 ± 2 mmol/l, p < 0.05) than those with normonatremia. Multivariate logistic regression after adjustment for basal serum sodium showed that advanced age (OR 1.15; 95% CI 1.03-1.27) and lower hemoglobin level (OR 0.64; 95% CI 0.43-0.94) were independently associated with hyponatremia. CONCLUSION: Hyponatremia is not infrequently associated with desmopressin use. Those with advanced age (≥65 years) and lower hemoglobin are at risk of desmopressin-associated hyponatremia and need to be carefully monitored.

The impact of adding low-dose oral desmopressin therapy to tamsulosin therapy for treatment of nocturia owing to benign prostatic hyperplasia.

PURPOSE: To evaluate the efficacy and safety of adding a low-dose oral desmopressin to tamsulosin therapy for treatment of nocturia in patients with benign prostatic hyperplasia (BPH). METHODS: Eligible patients with BPH and nocturia ≥2/night were randomly allocated to two treatment groups; the first of which received 3-month treatment scheme of daily oral dose of tamsulosin OCAS 0.4 mg and desmopressin MELT 60 mcg (D/T group), while the second one received tamsulosin OCAS 0.4 mg only (T group). Patients were followed on monthly basis and changes in the parameters from baseline to 3 months after treatment were assessed on I-PSS/QoL questionnaire, 7-day voiding diary, urinalysis, serum sodium, abdominal ultrasonography and uroflowmetry. RESULTS: A total of 248 patients were included within the study; 123 patients in the combined D/T group and 125 patients in T group. The frequencies of night voids decreased by 64.3% in D/T group compared to 44.6% in T group. The first sleep period, significantly increased from 82.1 to 160.0 min and from 83.2 to 123.8 min in D/T and T group, respectively; and significant differences between both groups were observed at the end of study (p < 0.001). I-PSS, QoL score, post-void residual urine volume and Q max were significantly improved with no statistical difference between both groups. No serious adverse effects were reported in both groups. CONCLUSION: The addition of low-dose oral desmopressin therapy to an α-blocker tamsulosin provides effective treatment for nocturia in patients with LUTS/BPH.

Comparison of incidence of hyponatremia between intranasal and oral desmopressin in patients with central diabetes insipidus.

Central diabetes insipidus (CDI), which is characterized by polyuria and polydipsia, is caused by a deficiency of the antidiuretic hormone arginine vasopressin (AVP). While CDI is treated with desmopressin, an analogue of AVP, the intranasal formulation is inconvenient and CDI patients reportedly prefer the oral formulation to the intranasal one. In Japan, intranasal desmopressin had been the only formulation for the treatment of CDI until 2012, when the desmopressin orally disintegrating tablet (ODT) was approved for treatment. In this study we analyzed 26 patients with CDI in whom intranasal desmopressin was switched to desmopressin ODT. The mean daily dose of intranasal desmopressin was 10 ± 8 µg/day, and that of desmopressin ODT was 142 ± 59 µg/day. The mean serum sodium levels were 140 ± 5 mmol/L and 140 ± 3 mmol/L with intranasal desmopressin and desmopressin ODT, respectively, and there were no significant differences between these values. The frequency of hyponatremia (<135 mmol/L) with intranasal desmopressin was 11.7% and that with desmopressin ODT was 7.6%, while the frequency of hyponatremia (<130 mmol/L) with intranasal desmopressin was 4.2% and that with desmopressin ODT was 1.3%. Statistical analyses revealed that incidence of hyponatremia was significantly decreased after the switch to desmopressin ODT. Thus, it is suggested that water balance is better controlled with desmopressin ODT than with intranasal desmopressin in patients with CDI.

A systematic review of the efficacy and safety of desmopressin for nocturia in adults.

PURPOSE: We systematically reviewed desmopressin as treatment for nocturia in generally healthy adults with a focus on benefits and harms. MATERIALS AND METHODS: After a literature search we identified 10 articles (2,191 patients) that met our inclusion criteria of parallel group design, randomized, controlled trials with information on at least 1 benefit or harm of desmopressin in patients with nocturia. We evaluated the quality of included trials based on The Cochrane Collaboration criteria, assessed heterogeneity using the I(2) statistic and performed random effects meta-analysis. RESULTS: Studies were generally of high quality, although 4 used an active run-in period to titrate the dose and exclude patients with adverse effects or who were nonresponders. Thus, they were at high risk for bias. Desmopressin doses of at least 25 mcg or greater decreased nocturnal voids and increased time to first void. A dose of 100 mcg provided just more than an hour of additional sleep before the first void compared with placebo as well as 0.72 fewer voids per night. Higher doses provided no significant increase in benefit. Hyponatremia (RR 5.1) and headache (RR 4.3) were the most common adverse effects. Serious adverse effects were rare. CONCLUSIONS: Desmopressin appears to offer a modest benefit for treating nocturia in generally healthy adults with adequate safety. The initial dose should be between 50 and 100 mcg. Higher doses should only be used with caution and a lower initial dose of 25 to 50 mcg is appropriate in elderly patients. All patients should be monitored for hyponatremia. The drug should be used with caution in patients with chronic lung disease due to the rare occurrence of respiratory failure. Additional well designed, adequately powered studies 1 or more years in duration are needed.

Desmopressin acetate (DDAVP)-associated hyponatremia and brain damage: a case series.

BACKGROUND: Desmopressin (DDAVP) is typically prescribed for central diabetes insipidus, von Willebrands disease and for enuresis. DDAVP-associated hyponatremia is a known complication of DDAVP therapy. The currently recommended treatment for this condition calls for discontinuing DDAVP as part of the initial therapy. This recommendation could lead to a water diuresis and potentially over-correction of the serum sodium. METHODS: The 15 patients in this case series developed symptomatic DDAVP-associated hyponatremia and were admitted to acute care hospitals. Thirty-eight percent presented with symptomatic hyponatremia and 62% developed symptomatic hyponatremia due to concomitant DDAVP and hypotonic intravenous fluid administration during a hospital stay. Group 1 patients (n = 13) were treated by withholding DDAVP and providing intravenous saline. Group 2 patients (n = 2) were treated by continuing DDAVP and providing DDAVP and intravenous hypertonic saline. RESULTS: Among Group 1 patients, in whom DDAVP was withheld as initial management of DDAVP-associated hyponatremia (n = 13), the mean change in serum sodium in the first 2 days of treatment was 37.1 ± 8.1 mEq/L. The ultimate outcome in this group was death in 23%, severe brain damage in 69% and moderate brain damage in 8%. In Group 2 patients, in whom DDAVP was continued (n = 2) as part of the initial management strategy, the mean change in serum sodium was 11.0 ± 0 mEq/L in the first 2 days. The ultimate outcome was survival without neurological sequelae in both cases. CONCLUSIONS: Discontinuing DDAVP in a patient with symptomatic DDAVP-associated hyponatremia can lead to rapid correction of the serum sodium and resultant severe neurological injury. In contrast, continuing the medication while correcting DDAVP-associated hyponatremia may lead to better outcomes by avoiding over-correction of the serum sodium. Thus, an alternative approach that we propose is to continue DDAVP as part of the initial management of this disorder.

Vasopressin receptor antagonists: from pivotal trials to current practice.

Heart failure is a growing health and economic problem in America, and outcomes continue to remain dismal, particularly for those presenting with acute heart failure syndrome (AHFS). In theory, arginine vasopressin antagonists (VRAs) could be useful in both acute and chronic heart failure, depending on which vasopressin receptor is targeted. Most studies of VRAs in heart failure have focused on V2 receptor antagonism, and to a lesser extent on combined V1a/V2 antagonism, due to the availability of appropriate agents and the unmet need of improving outcomes in AHFS. These agents are particularly attractive as adjunctive or alterative agents in AHFS because of their ability to produce a substantial diuresis without some of the drawbacks intrinsic to loop diuretics. While VRAs have been shown to ameliorate signs and symptoms of congestion when added to standard care, the largest trial of these agents showed no improvement in long-term morbidity, mortality, or hospitalization rates when added to standard care. This article reviews the mechanism of action of VRAs, the relevant clinical trials data, and current recommendations for clinical use, and suggests future directions for study of these agents in patients with heart failure.

Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study.

PURPOSE: We investigated the efficacy and safety of 50 and 75 µg desmopressin orally disintegrating tablets in men with nocturia (2 or more nocturnal voids). MATERIALS AND METHODS: In this 3-month, randomized, double-blind, parallel study 50 and 75 µg desmopressin were compared with placebo. The co-primary efficacy end points were changes from baseline in mean number of nocturnal voids and proportions of patients achieving at least a 33% reduction from baseline in nocturnal voids (33% responders) during a 3-month treatment period. RESULTS: The full analysis set comprised 385 men (age range 20 to 87 years). The 50 and 75 µg doses significantly reduced the number of nocturnal voids (-0.37, p <0.0001 and -0.41, p = 0.0003, respectively) and increased the odds of a 33% or greater response (OR 1.98, p = 0.0009 and OR 2.04, p = 0.0004, respectively) compared with placebo during 3 months. Desmopressin 50 and 75 µg increased the time to first void from baseline by approximately 40 minutes compared to placebo (p = 0.006 and p = 0.003, respectively). The response to desmopressin was seen by 1 week of treatment and was sustained. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated as only 2 subjects (age 74 and 79 years) on 50 µg had a serum sodium level of less than 130 mmol/L (vs 9 subjects on 75 µg). CONCLUSIONS: Desmopressin (orally disintegrating tablet) is an effective and well tolerated treatment for men with nocturia. Treatment with 50 µg desmopressin, the minimum effective dose, provided sustained improvement of nocturia throughout the study and meaningful benefits to patients with an improved safety profile.

Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study.

PURPOSE: Previous studies suggest a lower dose of desmopressin orally disintegrating tablet may be effective in females compared to males with nocturia. We confirm the efficacy and safety of 25 µg desmopressin orally disintegrating tablet compared to placebo in female patients. MATERIALS AND METHODS: In this 3-month, randomized, double-blind, parallel group study 25 µg desmopressin once daily was compared to placebo in women with nocturia (2 or more nocturnal voids). The co-primary efficacy end points were change from baseline in mean number of nocturnal voids and proportion of patients achieving at least a 33% reduction from baseline in the mean number of nocturnal voids (33% responders). RESULTS: The full analysis set comprised 261 patients (age range 19 to 87 years). Desmopressin significantly reduced the mean number of nocturnal voids and increased the odds of a 33% or greater response compared to placebo during 3 months, assessed by longitudinal analysis (-0.22, p = 0.028 and OR 1.85, p = 0.006, respectively). Desmopressin increased the mean time to first nocturnal void by 49 minutes compared to placebo at 3 months (p = 0.003). The response to desmopressin was seen by week 1 of treatment and was sustained throughout the trial. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated. Serum sodium levels remained greater than 125 mmol/L throughout the trial and 3 transient decreases to less than 130 mmol/L were recorded. CONCLUSIONS: At a dose of 25 µg, desmopressin orally disintegrating tablet is an effective and well tolerated treatment for women with nocturia. Treatment provides rapid and sustained improvement in nocturia and quality of life.

Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Desmopressin orally disintegrating tablet (ODT) 60-240 µg has proved an effective and well-tolerated antidiuretic treatment in male and female patients with nocturia. The main adverse event is hyponatraemia. Recent studies suggest that female patients are more sensitive to desmopressin ODT, achieving the same efficacy at lower doses than male patients. The study demonstrates the efficacy of desmopressin ODT in male and female Japanese patients with nocturia. It provides further evidence that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males. Tailoring the dose according to gender provides an improved therapeutic window with the benefits of a decreased risk of hyponatraemia without compromising efficacy. OBJECTIVES: To establish the dose-response efficacy of desmopressin in a Japanese patient population for the treatment of nocturia. To explore gender differences in sensitivity to desmopressin in Japanese patients with nocturia. PATIENTS AND METHODS: A phase II multicentre, randomized, placebo-controlled, double-blind, parallel-group, comparative clinical trial was conducted. Subjects aged 55-75 years, with a mean of ≥2 voids per night, were included and randomized to receive placebo or one of four doses of desmopressin orally disintegrating tablet (ODT): 10 µg, 25 µg, 50 µg or 100 µg. The dose-response relationship of pharmacodynamic variables measured after a single dose of desmopressin administered to water-loaded subjects (treatment period 1) was compared with the primary clinical endpoint of change from baseline in mean number of nocturnal voids, after 28 days of desmopressin treatment (treatment period 2). RESULTS: A total of 116 patients were treated in treatment period 1 of whom 113 qualified for treatment period 2, and 111 completed the study. In treatment period 1 a dose-response relationship was observed, both overall and in each gender group. Overall, the duration of antidiuretic action (DOA; time with urine osmolality >200 mOsm/kg) for the 25, 50 and 100 µg doses was 2 h (P = 0.010), 3.45 h (P < 0.001) and 5.74 h (P < 0.001), respectively; all statistically significant compared with placebo. Female patients were found to be more sensitive to desmopressin; DOA in female patients was longer than in male patients after desmopressin 25 and 50 µg. Extrapolation suggests that male patients require ∼58 µg to achieve similar DOA to females receiving 25 µg. A dose-response relationship was also seen in treatment period 2 for the group overall with a greater reduction in mean number of nocturnal voids from baseline to day 28 at higher doses, and with significant reductions in the 25- (P = 0.015) 50- (P < 0.001) and 100-µg (P = 0.001) dose groups compared with placebo. Similar dose-response relationships were also seen when the data were analysed by gender. Desmopressin ODT was well tolerated with no serious or severe adverse events. CONCLUSIONS: A dose-response relationship for desmopressin ODT was shown in a population of Japanese patients with nocturia. The study suggests that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males, indicating a gender-specific therapeutic window with a decreased risk of hyponatraemia without compromising efficacy on reduction of nocturnal voids. Further dose-finding studies are planned to confirm the recommended dose for the treatment of nocturia in a Japanese patient population.